KEAP1在肝癌对索拉非尼耐药中的作用和相关机制研究

肝癌是全球最常见恶性肿瘤之一，具有多耐药和预后差的特性。索拉非尼是中晚期肝癌的一线治疗药物，但是耐药性严重限制了其疗效。目前对肝癌耐药产生的分子机制还缺乏完整的认识。本课题组通过CRISPR/Cas9基因组文库在肝癌细胞株中筛选，首次发现KEAP1是影响肝癌细胞对索拉非尼敏感性一个全新的未知调控因子。KEAP1通过泛素化修饰底物蛋白调控多条信号通路，其中包括与肿瘤耐药性产生相关的Nrf2/ARE和IKKβ/NF-κB，但负责介导KEAP1抑制肝癌对索拉非尼耐药的关键机制并不清楚。基于现有的研究基础，本项目拟通过体外和体内实验，围绕KEAP1在肝癌对索拉非尼耐药性产生中的关键作用，以及介导其生物学效应的分子机制展开研究，是一项具有独创性和新颖性的研究工作，并有良好的研究积累。通过本项目研究有望揭示肝癌索拉非尼耐药的关键作用基因及信号通路，从而为新的药物作用靶点选择提供依据。

Hepatocellular carcinoma is one of the most common malignancies in the world, with multiple resistance and poor prognosis. Sorafenib is the first-line treatment for advanced HCC, but drug resistance severely restrict its efficacy. By now, the molecular mechanism of Sorafenib resistance is lack of well understanding. In this study, by using CRISPR/Cas9 genome library screening, KAEP1 was discovered as a totally new unknown factor of the sensitivity of hepatoma cells to Sorafenib. KEAP1 regulates multiple signaling pathways by ubiquitinating substrate proteins, including Nrf2/ARE and IKKβ/NF-κB, which are associated with drug resistance of tumor, but the key mechanism of KEAP1 inhibits Sorafenib resistance is unclear. Based on previous reports and existing results, with ingenuity and novelty of this work，the role of KEAP1 in Sorafenib resistance of HCC was investigated in vitro and in vivo, and the underlying mechanism was also explored. Our research is expected to reveal the key genes and signal pathways of Sorafenib resistance in HCC, and provide new targets in HCC treatment.